The Antibiotic Rifampin to Reduce High Levels of Blood and Urine Calcium in IIH

Sponsor

The Hospital for Sick Children (Other)

Overall Status

Recruiting

CT.gov ID

NCT03384121

Collaborator

Children's Hospital of Philadelphia (Other), Canadian Institutes of Health Research (CIHR) (Other), Cures Within Reach (Other)

Enrollment

Location

Arm

46.3

Anticipated Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Idiopathic infantile hypercalcemia(IIH) is a rare,genetic disorder of mineral metabolism. Biallelic loss of functions mutations of CYP24A1, the gene encoding the 24-hydroxylase enzyme that represents the principal pathway for inactivation of vitamin D metabolites, cause the most common and severe form of IIH.Investigators have preliminary data supporting a novel therapeutic approach to suggest rifampin as an investigational drug to induce over-expression of CYP3A4, an important enzyme that provides an alternate catabolic pathway for inactivation of vitamin D metabolites. In this study, investigators will recruit 5 patients with biallelic inactivating mutations of CYP24A1. Participants will be followed prospectively for a total 6-11 months. This will include 2 months of observation, 2 months of receiving the starting dose of rifampin, followed by 2 month washout phase. Efficacy of the starting dose of rifampin will be determined prior to proceeding only in non responders to the escalation dose of rifampin 10mg/kg/day.

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Infantile Hypercalcemia - Mild Form	Drug: Rifampin 150 mg, 300 mg capsules and 25 mg/mL oral suspension	Phase 1

Detailed Description

Idiopathic infantile hypercalcemia(IIH) is a rare,genetic disorder of mineral metabolism characterized by severe hypercalcemia and/or hypercalciuria, suppressed serum levels of parathyroid hormone (PTH), elevated levels of the active vitamin D metabolite, 1,25(OH)2D, and nephrocalcinosis. Biallelic loss of functions mutations of CYP24A1, the gene encoding the 24-hydroxylase enzyme that represents the principal pathway for inactivation of vitamin D metabolites, cause the most common and severe form of IIH.

Investigators have preliminary data supporting a novel therapeutic approach to suggest rifampin as an investigational drug to induce over-expression of CYP3A4, an important P450 microsomal enzyme that is expressed in the liver and intestine. When CYP3A4 is induced, the increased enzyme activity provides an alternative catabolic pathway for inactivation of vitamin D metabolites. The purpose of this study is to obtain results and support for an open label, escalating dose study to assess the effect, safety, and tolerability of once daily oral rifampin for two months in participants with IIH due to inactivating mutations in CYP24A1.

In this study, Investigators will recruit 5 patients with biallelic inactivating mutations of CYP24A1. Participants will be followed prospectively for a total 6-11 months. This will include 2 months of observation, 2 months of receiving the starting dose of rifampin, followed by 2 month washout phase. Efficacy of the starting dose of rifampin will be determined prior to proceeding only in non responders to the escalation dose of rifampin 10mg/kg/day. In addition to determining if this treatment is efficacious in reducing elevated serum and urinary calcium in patients, it will be determined if there is a dose effect of rifampin. As well, detailed measurements of vitamin D metabolites will determine if rifampin reduces hypercalcemia through increased CYP3A4 activity.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

5 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

This is a phase 1 pilot study whereby all participants start the study at a starting dose 5mg/kg/day (at study visit 2) for two months, and those that do not respond to 5mg/kg/day, otherwise known as non-responders, will receive a higher dose of 10 mg/kg/day (at study visit 4) for another two months. Recruited patients will be followed prospectively for a total of 6-11 months. This will include 2 months of observation, 2 months of receiving the starting dose of rifampin of 5mg/kg/day with a maximum dose of 600mg/day followed by a 2 month washout phase. The efficacy of the starting dose of rifampin will be determined prior to proceeding only in non-responders to the higher dose of 10 mg/kg/day with a maximum dose of 600 mg/day.This is a phase 1 pilot study whereby all participants start the study at a starting dose 5mg/kg/day (at study visit 2) for two months, and those that do not respond to 5mg/kg/day, otherwise known as non-responders, will receive a higher dose of 10 mg/kg/day (at study visit 4) for another two months. Recruited patients will be followed prospectively for a total of 6-11 months. This will include 2 months of observation, 2 months of receiving the starting dose of rifampin of 5mg/kg/day with a maximum dose of 600mg/day followed by a 2 month washout phase. The efficacy of the starting dose of rifampin will be determined prior to proceeding only in non-responders to the higher dose of 10 mg/kg/day with a maximum dose of 600 mg/day.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Rifampin to Reduce Elevated Levels of Blood and Urine Calcium in Patients With Idiopathic Infantile Hypercalcemia

Actual Study Start Date :

Feb 22, 2018

Anticipated Primary Completion Date :

Dec 31, 2021

Anticipated Study Completion Date :

Dec 31, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rifampin All subjects	Drug: Rifampin 150 mg, 300 mg capsules and 25 mg/mL oral suspension Starting Dose (V2): 5 mg/kg/day (max 600mg/day) orally for 2 months followed by a 2 month washout period V4: After washout period, only Non-responders will escalate dose to 10 mg/kg/day (max 600mg/day) orally for 2 months Other Names: Rifadin, Rofact, Rifampicin

Arm

Intervention/Treatment

Experimental: Rifampin

All subjects

Drug: Rifampin 150 mg, 300 mg capsules and 25 mg/mL oral suspension

Starting Dose (V2): 5 mg/kg/day (max 600mg/day) orally for 2 months followed by a 2 month washout period V4: After washout period, only Non-responders will escalate dose to 10 mg/kg/day (max 600mg/day) orally for 2 months

Other Names:

Rifadin, Rofact, Rifampicin

Outcome Measures

Primary Outcome Measures

Change in Serum Calcium [40 weeks]
Measured at baseline and every 2 months (8 weeks)
Change in Serum Parathyroid Hormone [40 weeks]
measured at baseline and every 2 months ( 8 weeks)
Change in Urinary calcium excretion [40 weeks]
Measured at baseline and every 2 months( 8 weeks)

Secondary Outcome Measures

Nephrocalcinosis [40 weeks]
Renal ultrasound performed before and after treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Months to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

all patients between 6 months- 17 years of age with the clinical phenotype of idiopathic infantile hypercalcemia
Biochemical evidence of this disorder: Serum calcium>upper limit of the reference age for range; high, 1,25 (OH)D; reduced PTH, reduced 24,25(OH)2D, and suppresses 24,1,25 (OH)2D, normal serum creatinine, AST, and ALT with or without
biallelic inactivating mutations of CYP24A1
mutations in newly published genes which are shown during the course of the study to cause an inappropriate increase in 1,25 (OH)2D

Exclusion Criteria:

Allergy to rifampin or related medications
Pregnancy or breastfeeding
Significant cardiac, hepatic, or endocrine comorbidities
Taking any medications/foods known to interact with CYP3A4 or 1,25 (OH)D
Parents or guardians or subjects who in the opinion of the Investigator may be non compliant with study schedules or procedures
Other comorbidities considered unsuitable by the investigator, including TB